The State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China; National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
The State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
Eur J Pharmacol. 2018 May 5;826:17-23. doi: 10.1016/j.ejphar.2018.02.036. Epub 2018 Feb 22.
Glucokinase was glucose sensor in hepatocytes and islet beta cells. It not only promoted glucose metabolism, but also advanced glucose-stimulated insulin secretion. Glucokinase activators had been reported as one kind of new potential drugs for treatment of type 2 diabetes. Compound 6-(5-(3-fluorobenzyloxy)-2-ethoxybenzamido) pyridine-3-carboxylic acid (SHP289-04) was found to increase glucokinase activity effectively by our lab. In order to demonstrate its effect of anti-diabetes, in vitro, human liver carcinoma cell line HepG2 was used to glucose consumption test, and pancreatic cell line NIT-1 was used to assess insulin secretion in response to different concentration of glucose (5 mmol/l and 20 mmol/l). Type 2 diabetes model KKA mice were chose to evaluate the pharmacodynamics of SHP289-04 in vivo. In hepatocytes, SHP289-04 could accelerate glucose consuming. In NIT cell line, it promoted glucose-stimulated insulin secretion at the 20 mmol/l of glucose. Moreover, it normalized oral glucose tolerance test and down-regulated blood lipid level in KKA mice. At the same time, it ameliorated function of islets and accelerated the ratio of beta cell/alpha cell mass, and also alleviated the fatty liver of KKA mice. Therefore, SHP289-04 as a glucokinase activator had the potential effect of diabetes treatment.
葡萄糖激酶是肝细胞和胰岛β细胞的葡萄糖传感器。它不仅促进葡萄糖代谢，还促进葡萄糖刺激的胰岛素分泌。葡萄糖激酶激活剂已被报道为治疗 2 型糖尿病的一种新型潜在药物。我们实验室发现，6-(5-(3-氟苄氧基)-2-乙氧基苯甲酰胺基)吡啶-3-羧酸（SHP289-04）可有效增加葡萄糖激酶活性。为了证明其抗糖尿病作用，在体外，用人肝癌细胞系 HepG2 进行葡萄糖消耗试验，用胰腺细胞系 NIT-1 评估不同浓度葡萄糖（5mmol/L 和 20mmol/L）刺激下的胰岛素分泌。选择 2 型糖尿病模型 KKA 小鼠来评估 SHP289-04 的体内药效学。在肝细胞中，SHP289-04 可加速葡萄糖消耗。在 NIT 细胞系中，它在 20mmol/L 的葡萄糖刺激下促进胰岛素分泌。此外，它还可使 KKA 小鼠的口服糖耐量试验正常化，并降低血脂水平。同时，它改善胰岛功能，加速β细胞/α细胞质量比，并减轻 KKA 小鼠的脂肪肝。因此，SHP289-04 作为葡萄糖激酶激活剂具有治疗糖尿病的潜力。
